Neuroendocrine Regulation of Appetitive Ingestive Behavior

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provided by Frontiers - Publisher Connector REVIEW ARTICLE published: 15 November 2013 doi: 10.3389/fnins.2013.00213 Neuroendocrine regulation of appetitive ingestive behavior

Erin Keen-Rhinehart 1*, Katelynn Ondek 1 and Jill E. Schneider 2

1 Department of Biology, Susquehanna University, Selinsgrove, PA, USA 2 Department of Biological Sciences, Lehigh University, Bethlehem, PA, USA

Edited by: Food availability in nature is often irregular, and famine is commonplace. Increased Alfonso Abizaid, Carleton University, motivation to engage in ingestive behaviors increases the chance of survival, providing Canada additional potential opportunities for reproduction. Because of the advantages conferred Reviewed by: by entraining ingestive behavior to environmental conditions, neuroendocrine mechanisms Hélène Volkoff, Memorial University of Newfoundland, Canada regulating the motivation to acquire and ingest food have evolved to be responsive to Tatsushi Onaka, Jichi Medical exogenous (i.e., food stored for future consumption) and endogenous (i.e., body fat University, Japan stores) fuel availability. Motivated behaviors like eating occur in two phases. The appetitive *Correspondence: phase brings animals into contact with food (e.g., foraging, food hoarding), and the Erin Keen-Rhinehart, Department of more reﬂexive consummatory phase results in ingestion (e.g., chewing, swallowing). Biology, Susquehanna University, 514 University Ave., Selinsgrove, PA Quantiﬁable appetitive behaviors are part of the natural ingestive behavioral repertoire 17870, USA of species such as hamsters and humans. This review summarizes current knowledge e-mail: [email protected] about neuroendocrine regulators of ingestive behavior, with an emphasis appetitive behavior. We will discuss hormonal regulators of appetitive ingestive behaviors, including the orexigenic hormone ghrelin, which potently stimulates foraging and food hoarding in Siberian hamsters. This section includes a discussion of the hormone leptin, its relation to endogenous fat stores, and its role in food deprivation-induced increases in appetitive ingestive behaviors. Next, we discuss how hormonal regulators interact with neurotransmitters involved in the regulation of ingestive behaviors, such as neuropeptide Y (NPY), agouti-related protein (AgRP) and α-melanocyte stimulating hormone (α-MSH), to regulate ingestive behavior. Finally, we discuss the potential impact that perinatal nutrient availability can have on the neuroendocrine regulation of ingestive behavior. Understanding the hormonal mechanisms that connect metabolic fuel availability to central appetite regulatory circuits should provide a better understanding of the neuroendocrine regulation of the motivation to engage in ingestive behavior.

Keywords: food hoarding, leptin, ghrelin, neuropeptide Y, maternal effects, gestational programming, hypothalamus, obesity

INTRODUCTION humans inhabit an environment with an overabundance of highly Although obesity was rare in the human population for thou- palatable, easily accessible food sources, transforming these once sands of years (Haslam, 2007), it is now one of the leading health beneficial adaptations into health liabilities. Therefore, under- issues worldwide and has been declared a global epidemic by the standing the basic neuroendocrine regulation of food and body World Health Organization (Caballero, 2007). Despite concerted fat storage and the mechanisms underlying the adaptations to efforts to solve this problem, obesity rates continue to rise world- a food-insecure environment is a central issue to understanding wide. To understand human ingestive behavior and the origins and combating the obesity epidemic (Ulijaszek, 2002). of this epidemic, it is useful to consider an evolutionary per- Human obesity studies typically focus on metabolism, adi- spective (Bronson, 1989; Neel, 1999; Prentice, 2005; Schneider, pogenesis, and meal patterns. Human foraging and hoarding 2006). Fluctuating food supply and famine have been a consistent behavior typically is dismissed as irrelevant to understanding threat to survival for most animals, including humans (Prentice, the health issues surrounding overeating, obesity, and diabetes. 2005). Selection pressures resulting from these fluctuations favor Some data is available, however, on food purchasing behavior, the ability to store energy sources on the body as fat and/or and these studies indicated that 85% of the energy content of the propensity to store food in the home. These abilities pro- the human diet consists of food purchased for consumption at vide a buffer against a variable or unpredictable food supply, and home (Ransley et al., 2003). These types of studies also con- thus allow animals to optimize reproductive success (Prentice, firm the well-known anecdote that purchasing food when food 2005; Schneider, 2006). These phenotypic properties are phys- deprived or “hungry” increases food purchasing, (Dodd et al., iologic (turning off unnecessary functions), metabolic (slowing 1977; Tom, 1983). In addition, obese individuals are likely to basal metabolic rate), behavioral (binge eating, food hoarding, purchase more food per person and more calorically dense food decreased physical activity), and adipogenic (generation of inter- (Ransley et al., 2003; Epstein et al., 2007). After foraging for food nal fat stores, (Prentice, 2005). In western, industrialized societies, at the grocery store, humans then store the food at home for

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future consumption in freezers and pantries (a.k.a. hoarding). Adrenal steroids (Stevenson and Franklin, 1970), and other pro- Efforts to understand the neuroendocrine differences responsible teins and peptides of the hypothalamic-pituitary-adrenal (HPA) for these incongruities between the behaviors of lean and obese axis significantly impact food intake (reviewed by Heinrichs and individuals have employed a variety of animal models. Richard, 1999; Bergonzelli et al., 2001). In addition, estradiol, Food intake is the most studied ingestive behavior, but other testosterone, progesterone, and other neuroendocrine factors of ingestive behaviors are likely to be important. In the long his- the hypothalamic-pituitary-gonadal axis (HPG) axis affect food tory of research in behavioral endocrinology, motivated behavior intake (reviewed by Wade, 1976; Schneider and Wade, 1999; is thought to be comprised of two main phases: the appetitive Schneider et al., 2002). Finally, the metabolic hormones, leptin, and the consummatory phases (Craig, 1918). Appetitive behav- insulin, glucagon, ghrelin, and glucagon-like peptide-I (GLP-I), iors are flexible, non-stereotyped responses that bring an animal as well as central factors, such as neuropeptide Y (NPY), agouti- into contact with a goal object, whereas consummatory behav- related protein (AgRP), cocaine and amphetamine-regulated iors are the final reflexive, stereotyped responses after decisions transcript (CART) and the melanocortins reliably affect consum- and efforts have been made to reach the goal object. Both appet- matory ingestive behavior in laboratory animals (reviewed by itive and consummatory behaviors can increase with hunger and Barsh and Schwartz, 2002; Zigman and Elmquist, 2003; Schwartz the desire immediately to consume food and to store energy. and Porte, 2005). Most recently, there has also been a push to Eaten food can be stored on the body as adipose tissue depots, understand the role of reward circuits and dopamine in the regu- while hoarded food is stored in the home or burrow for later lation of ingestive behavior (Abizaid et al., 2006b; Hommel et al., consumption during energetic deficits. The important distinc- 2006; Abizaid, 2009). We shall attempt to review the contributions tion lies in the fact that consummatory behaviors also reflect the of each of these three systems to the neuroendocrine regulation of ability to perform motor actions. Therefore, measures of food consummatory ingestive behavior. intake can be confounded by limits on the ability of the animal to eat or digest food, or by many other postingestional cues. THE ARCUATE PERSPECTIVE ON THE REGULATION OF By contrast, appetitive behaviors are a more “pure” reflection of CONSUMMATORY INGESTIVE BEHAVIOR motivation for acquiring fuels either for eating or calorie storage. The often co-localized orexigenic neuropeptides AgRP and NPY Some appetitive ingestive behaviors occur at different times than are the major products of the Arc that stimulate food intake consummatory behaviors, and appetitive behaviors most useful (Kalra et al., 1999; Morton and Schwartz, 2001; Ellacott and Cone, for scientific study are those that can occur even in the absence of 2004). The anorexigenic neuropeptide α-melanocyte stimulat- changes in food intake (Bartness and Clein, 1994; Bartness, 1997; ing hormone (α-MSH), a cleavage product of the proopiome- Buckley and Schneider, 2003). For example, hungrier animals lanocortin (POMC) gene, and CART are thought to oppose the initiate meals sooner, avidly consume an unpalatable substance, effects of NPY and AgRP (reviewed by Zigman and Elmquist, make more effort to gain access to food, and hoard more food in 2003; Schwartz and Porte, 2005). According to the Arc perspec- their home or burrow (reviewed by Keen-Rhinehart et al., 2010; tive, anorexigenic and orexigenic neuron populations in the Arc Bartness et al., 2011; Schneider et al., 2013). This review will respond to changes in the availability of oxidizable metabolic focus on appetitive ingestive behaviors that: (1) are easily quan- fuels, body fat stores, and/or peripheral hormones such as glu- tified, (2) occur separate in time and space from consummatory cocorticoids, ghrelin, and leptin (Baskin et al., 1999; Cone et al., behaviors, (3) are controlled by different chemical messengers, 2001). Peripheral hormones bind to receptors on Arc NPY/AgRP neural substrates, and environmental stimuli than consumma- and POMC/CART neurons, affecting gene transcription (Coppari tory behaviors, and (4) are able to provide an indication of et al., 2005; Elmquist et al., 2005) and the synaptic inputs to the animals’ internal motivational state. The neuroendocrine the Arc neurons (reviewed by Zigman and Elmquist, 2003; Gao mechanisms that control consummatory ingestive behavior (food et al., 2007; Gyengesi et al., 2010; Briggs and Andrews, 2011; Eckel, consumption) are relatively well studied (for reviews see: Kalra 2011). et al., 1999; Abizaid and Horvath, 2012; Kageyama et al., 2012). Although the plethora of evidence in support of the “arcuate After a brief review of the neuroendocrine regulation of con- perspective” seems to provide a simple, well-constructed model summatory ingestive behavior, this review will focus mostly for the regulation of food intake at first glance, many other stud- on the neuroendocrine basis for appetitive behavior, with a ies indicate that the Arc is neither necessary nor sufficient for major emphasis on food hoarding as a quintessential appetitive the regulation of ingestive behavior (Grill, 2010). For example, behavior. neonatal Arc ablation does not disrupt food intake (Coppari et al., 2005),nordoesadultArcablationhaveaneffectiftheani- NEUROENDOCRINE REGULATION OF CONSUMMATORY mals are given GABA agonists in the parabrachial nucleus [PBN INGESTIVE BEHAVIOR (Wu et al., 2009)]. In addition, food intake increases when the Historically, the majority of ingestive behavior studies have used leptin receptor (LepR) is deleted outside the Arc and when orex- laboratory rats or mice as model systems, measuring the food igenic neuropeptides are injected in extra-arcuate regions of the consumption of animals housed in isolation. Therefore, it is use- brain (Faulconbridge et al., 2005; Dhillon et al., 2006; Musatov ful to review these data as a starting point for understanding et al., 2007). The “arcuate perspective” also fails to incorpo- the neuroendocrine control of ingestive behavior. Many neu- rate extra-Arc populations of NPY, AgRP, and α-MSH neurons roendocrine factors affect food intake in laboratory animals in areas such as the dorsomedial hypothalamus (DMH), ven- (reviewed by Schneider and Watts, 2002; Schneider et al., 2012). tromedial hypothalamus (VMH), paraventricular nucleus of the

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hypothalamus (PVN) and lateral hypothalamus (LHA), as well as and then ingestive behavior resumes once the stressful situation how these cells are connected to the PBN, the dorsomotor nucleus has been resolved (Sapolsky et al., 2000). This sequence of events of the vagus (DMV) and the nucleus of the solitary tract (NTS) facilitates the reinstatement of energy balance by replacing the in the hindbrain, that are responsible for the motor movements energy expended on the fight-or-flight response (Sapolsky et al., necessary for food intake (Zheng et al., 2010).Ithasalsobeen 2000). Stress responses are energetically expensive, and the ability demonstrated that peripheral sensory information reaches the to replenish lost energy is affected by fluctuating variables such as diencephalon via the afferent visceral-central pathway and that food availability, mate availability, and ambient temperature mak- vagal afferent NTS neurons connecting directly to pre-oral motor ing the metabolic fuel availability a significant modulator of the neurons of the reticular formation are both essential and suffi- effects of CRH and glucocorticoids on behavior. cient for consummatory ingestive behavior (reviewed by Grill, 2010). Therefore, examining the role of these extra-Arc areas in ROLE OF REWARD CIRCUITS IN THE REGULATION OF CONSUMMATORY the regulation of consummatory ingestive behavior in the future INGESTIVE BEHAVIOR should provide a more complete understanding of the neural Further complexity in the neuroendocrine regulation of consum- circuitry controlling food intake. matory ingestive behavior is afforded by the involvement of the mesolimbocortical dopaminergic (DA) system, which includes ROLE OF THE HPA AXIS IN THE REGULATION OF CONSUMMATORY the nucleus accumbens, ventral tegmental area (VTA), and parts INGESTIVE BEHAVIOR of the amygdala. This system is implicated in modulating behav- It has long been known that stress and adrenal steroids affect iors such as learning, appetite, motivation and reward, as well as food consumption (Stevenson and Franklin, 1970). The HPA the willingness to work to access highly palatable foods (reviewed axis provides critical input to the neuroendocrine mecha- by Abizaid, 2009). Partly because of the overabundance of data nisms that regulate energy intake, storage, and expenditure supporting the hypothesis that obesity can be attributed to an (reviewed by Heinrichs and Richard, 1999). Within the HPA axis, addiction to food (Stice et al., 2012; Volkow et al., 2013), numer- corticotropin-releasing hormone (CRH) regulates the secretion ous studies have been conducted to investigate the connections of adrenocorticotropic hormone (ACTH), which controls the between metabolic hormones and central reward circuits (for secretion of adrenal steroids. Food deprivation decreases CRH review see Hirasawa et al., 2007; Pandit et al., 2011; Schellekens expression in the PVN (Brady et al., 1990). CRH plays an et al., 2012; Volkow et al., 2013).Forexample,leptinisappar- anorexigenic role in the basal regulation of food intake (Karolyi ently able to reduce appetite by diminishing the rewarding value et al., 1999). Although CRH is anorectic, glucocorticoids are of food. Studies supporting this notion show that increased leptin orexigenic, and obesity does not occur in their absence. For signaling specifically in the VTA decreases food intake and firing example, lesion-, diet-, NPY-, and leptin gene mutation-induced rates of DA neurons while treatments that impair leptin signal- obesity are reversed by adrenalectomy or by lack of glucocor- ing in the VTA increase DA neuronal firing rates, food intake and ticoids caused by shutting down the HPA axis (Bruce et al., the proclivity to ingest highly palatable foods (Fulton et al., 2002, 1982; Romsos et al., 1987; Stanley et al., 1989; Bray et al., 1992; 2006; Hommel et al., 2006; Abizaid, 2009). Ghrelin also appears to Feldkircher et al., 1996). modulate food intake via action in the VTA, and peripheral ghre- HPA axis hormones and neuropeptides are highly conserved lin treatment increases DA turnover, food intake and synapses across a wide array of species, with regard to both chemi- connecting with DA cells in the VTA in mice (Abizaid et al., cal structure and the effects on the ingestive behavior (Landys 2006a,b). Therefore, the midbrain has emerged as an important et al., 2006). The CRH gene sequence is highly homologous in site for the integration of information about peripheral metabolic organisms from fish to mammals, and central CRH treatment factors in the service of ingestive behavior regulation. decreases food intake in all classes of vertebrates tested to date (Carr, 2002) without increasing plasma glucocorticoids, unlike APPETITIVE INGESTIVE BEHAVIOR peripheral administration that increases both glucocorticoid lev- It is typically assumed that if a substance applied to the brain els and food consumption (Glowa et al., 1992). Although CRH is affects food intake, it must function in the service of energy bal- anorexigenic, glucocorticoids typically stimulate food consump- ance. One must also consider the possibility that these factors tion (Dallman et al., 1993, 2004) and provide negative feedback may have altogether different purposes for an animal in a nat- to inhibit CRH production and release. Thus, orexigenic effects of uralistic setting. It is unlikely that these other functions will be glucocorticoids could occur via direct effects on appetite regula- observed in laboratory experiments studying singly housed ani- tory mechanisms or via indirect effects by inhibiting the synthesis mals with unlimited food and few prospects for species-typical and release of CRH (reviewed by Heinrichs and Richard, 1999). behaviors or opportunities for energy expenditure. For example, The opposing effects of CRH and glucocorticoids are likely part experimentally induced increases in food consumption in an indi- of an adaptive response to stress (Sapolsky et al., 2000). Stress vidually housed animal may actually affect motivation that would causes the release of adrenaline and CRH, which inhibit ingestive stimulate foraging, hoarding, or hunting behavior in a more natu- behaviors and trigger “fight-or-flight” behaviors, increasing the ralistic setting. Experimentally induced decreases in hunger might likelihood of survival. Increases in CRH directly stimulate sym- increase mate searching, courtship, mating, nest building, incu- pathetic tone and the uptake of oxygen and metabolic fuel by the bation, migration, or hibernation. In nature, ingestive behavior brain and muscles. The resulting rise in glucocorticoids inhibits must be balanced with other priorities such as predator avoid- CRH via action on central receptors to turn off the stress response, ance, food availability, and copulation. Regardless of the animal

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model, experiments examining only consummatory ingestive food deprivation with prolonged increases in food hoarding but behavior in isolated animals might support the idea that 40 or not food intake permits the disentanglement of the mechanisms more redundant peptide systems regulate this one variable, food underlying appetitive and consummatory ingestive behaviors that intake. Therefore, manipulations of environmentally relevant are inextricably intertwined in other rodent models (for review variables (e.g., nutrient availability) to determine how these affect see: Keen-Rhinehart et al., 2010; Bartness et al., 2011). Over the the expression of appetitive behaviors (those other than food past two decades, studies using Siberian hamsters have thoroughly intake) are necessary to provide a more complete understanding and systematically determined how appetitive ingestive behav- about the neuroendocrine regulation of the motivation to eat. iors are affected by fasting, diet dilution and lipectomy as well as treatment with orexigenic factors such as NPY, Y1R agonists, APPETITIVE BEHAVIORS: INDICATORS OF MOTIVATION AgRP, and ghrelin and anorexigenic factors such as leptin, MT-II, Ingestive behavior is multifaceted and cannot be accurately cap- CCK, and Y1R antagonists (Bartness and Clein, 1994; Bartness tured by measuring the amount of food consumed because swal- et al., 2011; Wood and Bartness, 1996a,b; Bartness, 1997; Day lowing is only one step in a long sequence of behaviors necessary and Bartness, 2003, 2004; Day et al., 2005; Keen-Rhinehart and for eating. Appetitive ingestive behaviors aim to ensure that suf- Bartness, 2005, 2007; Keen-Rhinehart et al., 2010; Teubner and ficient energy will be available for future energetic needs (Craig, Bartness, 2010; Teubner et al., 2012). 1918; Everitt et al., 1984). Studying appetitive ingestive behaviors is the preeminent way to assess the internal motivation to con- APPETITIVE BEHAVIOR REGULATION: BEYOND THE ARCUATE sume food. Furthermore, the study of appetitive behaviors can PERSPECTIVE provide information about how environmental factors such as As mentioned earlier, many investigators in the field of ingestive nutrient availability impact behavioral priorities. behavior consider the Arc to be the hub for the regulation of food In certain well-designed experimental paradigms, appetitive intake. Therefore, initial experiments regarding the neuroen- behaviors are separable from consummatory behaviors, and the docrine mechanisms that regulate appetitive ingestive behaviors mechanisms underlying these two phases of ingestive behaviors focused on this area as a starting point. As mentioned previously, can be studied separately. The significance of the separation of food deprivation in Siberian hamsters causes large increases in the appetitive and consummatory phases of ingestive behavior food hoarding with little to no effects on food intake (Bartness lies in the fact that the two phases are initiated by different envi- and Clein, 1994; Bartness, 1997). The orexigenic hormone ghrelin ronmental conditions via various neuroendocrine factors that act is increased in response to food deprivation in hamsters, simi- on separate neural substrates (reviewed by Ball and Balthazart, larly to other animals (Ariyasu et al., 2001; Asakawa et al., 2001; 2008). One of the clearest examples of the separate neuroen- Keen-Rhinehart and Bartness, 2005). When hamsters are treated docrine regulation of these behavioral phases is the control of with ghrelin at doses that produce circulating ghrelin concentra- consummatory but not ingestive behaviors by the brain stem tions similar to a 48 h fast, there is an initial, small increase in (Grill and Smith, 1988; Grill and Kaplan, 2001, 2002). This is skill- food intake followed by a massive, long-term increase in food fully illustrated in experiments showing that decerebrate rats have hoarding behavior (Keen-Rhinehart and Bartness, 2005). We now intact neuroendocrine regulation of intraoral food intake in the know that both food deprivation and ghrelin stimulate Arc NPY absence of the ability to express any appetitive behaviors (Grill and AgRP neurons (Hahn et al., 1998; Mercer et al., 2000), trig- and Kaplan, 1992, 2001, 2002; Grill and Hayes, 2009). gering the release of these orexigenic neuropeptides (Chen et al., To understand the neuroendocrine mechanisms regulating 2004). As one would expect, central treatment with either of appetitive ingestive behaviors and thus the motivation to eat, it these orexigenic factors trigger marked increases in food hoard- is necessary to look beyond the commonly studied rats and mice ing with minimal increases in food intake [i.e., NPY (Day et al., to other animal models where appetitive behaviors such as food 2005; Keen-Rhinehart and Bartness, 2005)andAgRP(Day and hoarding are separable from food consumption. While rats and Bartness, 2004)]. Conversely, the anorexigenic hormone leptin mice typically increase food intake in response to fasting or food is postulated to act on LepR-expressing hypothalamic neurons restriction (Ross and Smith, 1953; Hill et al., 1983, 1984), ham- (Baskin et al., 1999; Elmquist, 2001) to reduce appetite by reduc- sters, like humans, reliably increase food hoarding instead of food ing expression of NPY and AgRP, and by increasing expression intake in response to energetic challenges (Silverman and Zucker, of anorexigenic neuropeptides like α-MSH (Baskin et al., 2001; 1976; Rowland, 1982; Billington et al., 1984; Bartness and Clein, Elmquist et al., 2005). In hamsters, central or peripheral treat- 1994; Bartness et al., 1995). In fact, Homo sapiens, unlike rats and ment with leptin reduces fasting- and ghrelin-induced increases mice, do not typically overeat in response to food deprivation in food hoarding behavior (Keen-Rhinehart and Bartness, 2008). (reviewed by Bartness et al., 2011).Peopledo,however,increase Because the expression of appetitive and consummatory inges- grocery shopping (foraging) and bring more food home (hoard- tive behaviors are separable in hamsters, the neural substrates ing) in correlation with the length of time since their last meal controlling food hoarding should be at least partially distinct (Dodd et al., 1977; Beneke and Davis, 1985; Mela et al., 1996). In from those that govern food intake. Several studies provide data addition, recent studies on overweight and obese children indi- in support of that hypothesis. For example, in Siberian hamsters, cate that a significant proportion of them exhibit disturbances Arc lesions diminish NPY-induced increases in food intake but in eating behaviors that include sneaking, hiding and hoarding not food hoarding (Dailey and Bartness, 2010), and studies using large quantities of food (Sonneville et al., 2013). Therefore, using Y1R- and Y5R-specific agonists indicate that NPY increases food a hamster model that responds to energetic challenges such as intake via action at the Y5 receptor but affects food hoarding by

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acting on the Y1 receptor (Keen-Rhinehart and Bartness, 2007). in appetitive ingestive behaviors that would make them an easy In addition, recent studies show that the pharmacological block- target. There is also some indication that the ability of leptin to ade of ghrelin activity attenuates, but cannot completely block, prevent fasting-induced increases in ingestive behavior is due in food deprivation-induced increases in food hoarding (Teubner part to activation of central CRH circuits (van Dijk et al., 1997). and Bartness, 2013; Teubner et al., 2013). Although the connection between the HPA axis and appetitive While Siberian hamsters typically exhibit increases in food ingestive behaviors has not been studied extensively in the ham- hoarding rather than food intake in response to energetic chal- ster model of food hoarding, such studies are likely to yield a lenges, there is initially a small increase in food intake before the great deal of useful information on the nexus between stress and large increase in food hoarding behavior. Exploiting the fact that ingestive behavior. increases in food intake appear more rapidly than increases in food hoarding, Teubner et al., differentiated the brain areas acti- REWARD CIRCUITS AND THE REGULATION OF APPETITIVE INGESTIVE vated concurrently with short-term increases in consummatory BEHAVIOR behavior from those activated later in conjunction with long-term Food intake is a motivated behavior, and animals find food, increases in appetitive behavior (Teubner et al., 2012). Combined especially highly palatable, calorically dense food, rewarding. central NPY + AgRP injection was associated with increased food Therefore, when examining the motivation to engage in ingestive intake and neuronal activation of the PVN and perifornical area behaviors, it is necessary to consider how reward circuits influ- (pFA) within 1 h post-injection, but increased food hoarding and ence the expression of appetitive ingestive behaviors. Studies in neuronal activation in the PVN, pFA, central nucleus of the amyg- Mongolian gerbils (Meriones unguiculatus) show that the act of dala (CeA) and the subzona incerta (SZI) were not detectible until hoarding food increases the activation of tyrosine hydroxylase 4–14 h post-injection. These data pinpoint two novel regulatory (TH)-containing cells in the nucleus accumbens, VTA, and LHA brain areas (CeA and SZI) that affect ingestive behavior. Despite (Yang et al., 2011). TH is the rate-limiting enzyme in the chem- the prevailing view that neurons in the Arc are critical for ingestive ical process of dopamine synthesis. In addition, both Mongolian behavior, NPY + AgRP co-injection did not activate Arc neurons gerbils and Brandt’s voles (Lasiopodomys brandtii)thatarecon- at any time when increased food hoarding was observed. sistent food hoarders exhibit food deprivation-induced increases This study also demonstrated that co-injection of sub- in food hoarding along with cellular activation in the VTA (Yang threshold doses of NPY and AgRP increases food hoarding in et al., 2011; Zhang et al., 2011). The association between the acti- Siberian hamsters, suggesting that there is a significant intercel- vation of DA neurons in the VTA with food hoarding suggests lular interaction between these two neuropeptides occurring as that animals with the propensity to hoard food or with previ- part of the regulation of food hoarding. Because AgRP is known ous food hoarding experience are likely to find food hoarding to cause long-term increases in food hoarding, AgRP may be pro- especially rewarding or reinforcing. Obviously, this, like the con- viding synergistic effects on NPY-induced food hoarding in the nection between the HPA axis and ingestive behavior regulation, CeA and SZI (Teubner et al., 2012), brain areas with Y1 as well as is greatly in need of further investigation. MC4 receptors (Lyons and Thiele, 2010). GESTATIONAL PROGRAMMING OF INGESTIVE BEHAVIOR ROLE OF THE HPA AXIS IN THE REGULATION OF APPETITIVE INGESTIVE The relatively recent, rapid increase in the prevalence of obesity BEHAVIORS has been attributed by some to environmental factors, including A great deal of research has been conducted on the effects of CRH the availability of highly palatable foods and “modern” lifestyles on consummatory ingestive behavior, all suggesting that CRH is involving less physical work, all of which have created an “obe- anorexigenic. Comparatively little has been done to determine sogenic” environment. It is also possible that characteristics of how CRH or other HPA axis factors affect appetitive ingestive the prenatal environment initiate organizational effects of hor- behaviors. Food deprivation decreases hypothalamic CRH mRNA mones that modulate neuroendocrine development to produce expression in several animal species (Brady et al., 1990; Glowa optimal adaptation of energy balance and ingestive behavior et al., 1992). In studies in which hunger motivation is taken to the anticipated postnatal environment. Several different syn- as the body weight loss that produces significant increases in onyms are used to describe the process by which changes in food hoarding, hunger motivation is decreased by adrenalectomy the mother’s environment lead to changes in fetal development and CRH treatment and increased by low doses of glucocorti- that have permanent effects in the offspring: gestational, fetal, coids, fasting, and low temperatures (Fantino and Cabanac, 1984; or maternal programming, or metabolic imprinting. Examples Cabanac and Richard, 1995; Cabanac et al., 1997; Gosselin and of factors in the mother that influence metabolism in offspring Cabanac, 1997; Michel and Cabanac, 1999). Studies in rats and include maternal food restriction, caloric, fat, carbohydrate or primates seem to indicate that CRH mediates a shift away from protein content of food, non-nutritional stress, and nutritional ingestive behaviors, affecting appetitive behaviors at lower doses status of the mother (reviewed by Armitage et al., 2004). In Homo than those at which food intake is impacted. In addition, studies sapiens, prenatal undernutrition leads to low birth weight (LBW) in anuran amphibians (toads) show that CRH treatment inhibits babies who are prone to develop metabolic syndrome, insulin the appetitive behavior of foraging by impairing the efficiency resistance, and obesity as adults (Hales and Barker, 2001; Cripps of visual stimuli to stimulate prey-catching behavior (Carr et al., et al., 2005). This relationship between LBW and later develop- 2002). This might be adaptive if, in the presence of a predator, the ment of obesity and metabolic syndrome has been replicated in hypothalamic stress response prevents the toads from engaging manydiversepopulationsaroundtheworld(Hales and Barker,

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2001; Gluckman et al., 2005). In addition, rapid neonatal catch- in programmed elevation of plasma ghrelin levels (reviewed by up growth caused by excessive appetite during the neonatal period Breton, 2013). Arc NPY and AgRP neurons in hypothalamic acts as an additional risk factor that further increases the risk of slices from adult nutrient-restricted offspring are more sensitive obesity (Hales and Barker, 2001; Gluckman et al., 2005; Vickers, to the stimulatory effects of ghrelin, which could indicate how 2007; Vickers et al., 2007). Because formula-fed infants typi- LBW offspring maintain elevated expression of ingestive behav- cally have an accelerated initial growth rate, formula feeding also ior throughout their lifespan (Yousheng et al., 2008). Together, increases the risk for becoming obese or overweight (Baird et al., these results suggest that appetite regulatory circuits can be 2005; Harder et al., 2005; Vickers, 2007; Vickers et al., 2007). The gestationally programmed to favor hyperphagia and storage of relationship between LBW and the later development of obesity energy as fat by developmental conditions that produce LBW and metabolic syndrome has been replicated animal models such offspring. as the rat, mouse, pig, sheep and guinea pig (for review see Hales One of the hypothesized mechanisms for long-term changes and Barker, 2001; Cripps et al., 2005; Gluckman et al., 2005). in the neuroendocrine regulation of ingestive behavior is an Interestingly, maternal obesity during pregnancy and gestational alteration in hormonal milieu at critical periods of develop- diabetes can also lead to offspring obesity (Muhlhausler, 2007; ment. As mentioned above, circulating ghrelin concentrations are Shankar et al., 2008). elevated in LBW offspring. In addition, leptin functions peri- From an ecological point of view, these maternal program- natally as a neurotrophic factor to facilitate the development ming effects might be adaptive (that is, they might improve of the neural circuits that govern metabolism, adipose tissue offspring survival and reproductive success) or maladaptive. One distribution and ingestive behavior (reviewed by Cottrell and hypothesis is that changes in maternal energy status generate sig- Ozanne, 2007, 2008; Breton, 2013). In rats and mice, there is nals in utero to communicate reduced energy availability. These a surge in plasma leptin concentration during postnatal days signals purportedly prepare the offspring for a postnatal envi- (PND) 4–12 (Ahima et al., 1998; Delahaye et al., 2008; Cottrell ronment with a low or unpredictable food supply. According to et al., 2009), the time when connections between hypothala- this idea, the maternal environment organizes energy balance and mic neurons are developing and leptin has no effect on appetite the central appetite regulatory circuits so that the offspring will (Ahima and Flier, 2000). Rodents exposed to reduced nutrient develop traits that will allow them to cope with that particular availability have reduced circulating leptin concentrations and environment (Gonzalez-Bulnes and Ovilo, 2012). A commonly increased hypothalamic LepR protein expression at birth (Cottrell reported phenomenon in mice, rats, sheep and primates is that et al., 2010; Coupe et al., 2010), as well as a delayed and/or LBW offspring have a propensity toward hyperphagia, efficient reduced leptin surge, which results in permanent changes in metabolism, and an increased inclination to store energy on the hypothalamic ingestive behavior regulatory circuits (Gluckman body as body fat (Cripps et al., 2005). These same animals might et al., 2005; Bautista et al., 2008). Recent studies provide fur- be better adapted to survive in an environment where food supply ther convincing evidence that leptin specifically promotes the is low or unpredictable. In an environment of energy abun- development of Arc neuronal projections, consistent with a role dance, however, they are likely to develop metabolic syndrome in brain development. Arc projections in mice are formed pri- and obesity. marily during the second week of postnatal life (reviewed by Ahima and Flier, 2000), developmentally similar to human third GESTATIONAL PROGRAMMING OF CONSUMMATORY INGESTIVE trimester of pregnancy. In leptin deficient (ob/ob) mice, these BEHAVIOR projection pathways regulating appetite are permanently dis- As mentioned previously, impaired prenatal nutrition causes off- rupted, causing Arc axonal densities one third to one fourth spring hyperphagia and obesity. Given the pervasive nature of that of controls (reviewed by Ahima and Flier, 2000). Reduced the “Arcuate perspective” on the control of ingestive behav- gestational nutrient availability permanently impairs the devel- ior, most studies on the gestational programming of appetite opment and connectivity of hypothalamic neurons that produce have focused on the effects of prenatal nutrient availability anorectic neuropeptides such as α-MSH and orexigenic neu- on orexigenic (i.e., ghrelin, NPY, and AgRP) and anorexigenic ropeptides such as NPY and AgRP from weaning through adult- (leptin and α-MSH) neuroendocrine factors. For instance, the hood (Muhlhausler et al., 2006; Delahaye et al., 2008; Coupe et al., stomach-derived orexigenic hormone ghrelin is elevated at birth 2010). Gestationally-restricted offspring also display resistance to in LBW offspring (Wang et al., 2007; Sahin et al., 2012)and the anorectic effects of peripheral leptin treatment in adulthood continues to be elevated into adulthood (Sahin et al., 2012). (reviewed by Breton, 2013). Therefore, leptin appears to be a crit- LBW offspring typically exhibit rapid catch-up growth facili- ical factor for the gestational programming of appetite regulatory tated by enhanced appetite shortly after birth (Coupe et al., circuits as well. 2010; Breton, 2013). Therefore, increased postnatal ghrelin likely Alterations in the Arc appetite regulatory network that plays a role in the rapid catch-up growth observed in most increase production of and sensitivity to orexigenic agents such as models of gestational programming. In rodents, 50% mater- NPY are clearly important for the programmed hyperphagia that nal food restriction during the second half of gestation results occurs in response to perinatal nutritional perturbations. As men- in LBW pups that, like human LBW infants, have significantly tioned above, the complex nature of ingestive behavior regulation increased ghrelin expression (Cortelazzi et al., 2003; Nagata makes is highly unlikely that just focusing on the Arc will be suffi- et al., 2011). These animals develop hyperphagia and obesity and cient to explain all the effects of gestational nutrient restriction demonstrate that catch-up growth among LBW offspring results on appetite regulation. Alterations in dopamine expression in

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the VTA may also be critically important because the reward efficient phenotype to increase the likelihood of reproductive suc- system is likely also to have gestationally programmed changes cess in an environment with a variable food supply (Prentice, that may influence ingestive behavior regulation. For example, 2005; Schneider, 2006). The overabundance of highly palatable, female LBW rats are more likely than non-restricted offspring easily accessible food sources present in the human environment to binge on sucrose when it is presented intermittently for lim- in developed countries has turned these adaptations into health ited amounts of time (unpublished observation). Therefore, fur- liabilities. Unfortunately, the list of neuropeptides that “regu- ther research into the contribution of reward circuitry to the late” appetite is now overwhelming, and most ingestive behavior mechanisms of gestational programming of appetite is clearly research continues to focus on the hypothalamic Arc nucleus as warranted. the command center for appetite regulation (reviewed by Barsh A plethora of data supports the hypothesis that perinatal nutri- and Schwartz, 2002; Zigman and Elmquist, 2003; Schwartz and tional disturbances majorly contribute to the development of Porte, 2005). adult obesity by altering appetite regulation to favor hyperphagia. Ingestive behavior regulation is far more complex than can This complex system of neuroendocrine factors undergoes a short be explained by studies conducted solely on the Arc nucleus. In period of plasticity during development when the nutritional addition, the study of the neuroendocrine regulation of appeti- environment programs this system to maximize an organism’s tive behaviors provides clues to the mechanisms responsible for chances for survival in its anticipated postnatal environment. the motivation to eat. This review seeks to demonstrate that Several rodent models have been used to study the mecha- while hypothalamic appetite regulatory circuits are important nisms responsible for perinatal appetite programming, including for the control of both appetitive and consummatory inges- the maternal food restriction, low protein, lactational overnu- tive behaviors, it is necessary to think more broadly than the trition, gestational diabetes, and high fat diet during pregnancy. “Arc perspective” by including systems such as the caudal hind- Currently, there is not a validated model for the study of gesta- brain, the HPA axis and central reward circuitry to provide a tional programming on appetitive ingestive behaviors. more complete picture of neuroendocrine regulation of ingestive behavior. APPETITIVE INGESTIVE BEHAVIORS Since the creation of the thrifty phenotype hypothesis by Hamsters have several unique characteristics that make them Neel in (1962), the maternal programming hypothesis of Jones ideal for studying the gestational programming of the regula- et al. in (1984), and it’s reiteration by Barker in (1994), under- tion of appetitive ingestive behaviors, including the fact that standing how nutrient availability during critical periods of hamsters utilize food hoarding as a significant part of their nat- development affects offspring appetite and energy balance has ural ingestive behavioral repertoire, and, unlike rats, hamsters been a major focus of obesity research (Jones et al., 1984; do not overeat after energetic challenges such as food depri- Barker, 1994; Neel, 1999). A great deal of research has been vation and pregnancy (Silverman and Zucker, 1976; Rowland, done to characterize the effects of reduced perinatal nutri- 1982; Billington et al., 1984; Bartness and Clein, 1994; Bartness ent availability on offspring consummatory ingestive behavior. et al., 1995). As mentioned above, the effects of gestational Although research has not previously been conducted to deter- nutrient availability on appetitive ingestive behaviors have yet mine how appetitive ingestive behaviors are impacted by maternal to be studied. Therefore, we recently endeavored to create a nutrient availability, future studies using hamsters as an ani- model of gestational programming in the hamster. In this model, mal model may provide critical information on the gestational pregnant hamsters are provided with daily food rations equal programming of neuroendocrine systems that regulate feeding to pre-pregnancy intake, preventing maternal food hoarding, a motivation. behavior naturally enhanced during the last half of pregnancy. Interestingly, male offspring of restricted mothers exhibit hyper- REFERENCES phagia and increased Arc NPY as well as decreased hoarding Abizaid, A. (2009). Ghrelin and dopamine: new insights on the peripheral regulation of appetite. J. Neuroendocrinol. 21, 787–793. doi: 10.1111/j.1365- behavior (unpublished observations). Further characterization 2826.2009.01896.x of this exciting new model of gestational programming should Abizaid, A., Gao, Q., and Horvath, T. L. (2006a). Thoughts for food: brain provide additional insights into the effects of prenatal environ- mechanisms and peripheral energy balance. 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